The objectives of this program are the determination of the mechanisms of action of antitumor agents and the utilization of such information in devising more effective ways of using the agents in experimental and clinical chemotherapy. Agents under study are 2-fluoro-9-beta-D-arabinosyladenine (F-AraA), 2-hydroxy-3-(3,3-dichloroallyl)-1,4-naphthoquinone (NSC-126771) and N-phosphonoacetyl-L-aspartate (PALA). F-AraA is a derivative of araA which is not subject to deamination (which limits the utility of araA as an antitumor agent) but which, like araA, is metabolized to the triphosphate and inhibits DNA synthesis. The metabolism and metabolic effects of F-araA will be examined in sensitive and resistant neoplasms. NSC-126771 is a quinone that interferes with electron transport; its toxicity is primarily due to reduction of pyrimidine nucleotide pools as a result of inhibition of DHO dehydrogenase. Studies will be performed on the kinetics of inhibition of the dehydrogenase and attempts will be made to use this agent more effectively in combination with other inhibitors of pyrimidine biosynthesis. PALA is known to inhibit pyrimidine biosynthesis by blocking aspartate transcarbamylase. PALA does not inhibit growth of P388 cells but does inhibit a line of P388 cells resistant to araC. We will explore the biochemical basis of the differences in response and other aspects of the metabolic effects of this agent.